1985 |
Hanck, Dorothy A |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Length-Dependent Phenomena in Cardiac Muscle |
0.929 |
1990 — 1999 |
Hanck, Dorothy A |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Kinetics of Cardiac Sodium Channel
sodium channel; heart pharmacology; arrhythmia; tetrodotoxin; heart Purkinje's fiber; electrophysiology; single cell analysis; antiarrhythmic agent; dogs;
|
0.958 |
1998 — 1999 |
Hanck, Dorothy A |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Cell Biology of Cardiac and Skeletal Muscle
This Program Project is organized to study the structure-function and modulation of cardiac Na channels and their participation in excitation of the heart. It is a more focused continuation of a long-standing research program in cell biology of muscle. It will include a project devoted to Na channel gating and its unique cardiac properties, a project to study Na channel permeation and selectivity, a project to determine mechanisms of drug interaction with the Na channel, a core for molecular biology, and a core for computer/electronics/mechanical services. It will employ physiological, pharmacologica1, biophysical, and molecular biological tools to develop a better understanding of ion channel structure-function and to integrate these insights into a progressively improving molecular structural model of the channels. This insight is important to define channels as drug targets and as participants in the pathophysiology of cardiac arrhythmias.
|
0.958 |
2000 — 2003 |
Hanck, Dorothy A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiac Channels--Targets of Drugs That Affect Kinetics
DESCRIPTION (Verbatim from Investigator's Abstract): Experiments proposed are aimed at determining structural similarities of drug binding sites between channel types for mibefradil (the only highly specific agent for T-type Ca channels known at the present time) and phenylalkylamines, the drug class that competes with mibefradil, and for which some structural information is available for L-type calcium channels. Three channels will be used, the T-type Ca channel alpha lH, as a high affinity target for mibefradil and a somewhat lower affinity target of verapamil, the voltage-gated Na channel, a very low affinity target for mibefradil but a moderate affinity target for verapamil, and HERG, a high affinity target for both mibefradil and verapamil. In each area, experiments proposed combine site-directed mutagenesis, electrophysiology, and molecular modeling. In addition, experiments are proposed that will establish the channel specific or common effects on kinetics that control the action and efficacy of these agents as therapeutic drugs.
|
0.958 |
2000 — 2003 |
Hanck, Dorothy A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Structural Bases of T-Type Calcium Channel Function
DESCRIPTION (adapted from the applicant's description): T-type Ca channels are present in a wide variety of cell types (cardiac myocytes, smooth muscle cells and neurons), and participate in various physiological functions such as pacemaking in heart and shaping bursting behavior in neurons. Their expression is upregulated under certain pathological conditions such as myocardial hypertrophy. This suggests that the T-type Ca channels may be involved in the progression of disease processes, or may be a valuable target of therapies. Recently, several isoforms of T-type channel pore-forming subunits have been cloned (alpha-1G, -1H, and -1I), providing an opportunity to study the molecular structure, physiology and pharmacology of this class of channels. In this proposal, the applicant proposes to investigate the structural basis of gating and ion selectivity/permeation of T-type Ca channels. Five specific aims are proposed to test two general hypotheses: (1) the steep voltage-dependence of inactivation from closed states of T-type Ca channels arises from activation gating, and (2) differences in selectivity between low- and high-voltage activated Ca channels and between Ca and Na channels arise from a focal set of differences in pore residues between these channel families. These experiments will use techniques of electrophysiology, mutagenesis and molecular modeling.
|
0.958 |
2007 — 2010 |
Hanck, Dorothy A. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiac Channels: Targets of Drugs That Affect Kinetics
DESCRIPTION (provided by applicant): Cardiac disease continues to be the leading cause of death in this country. Drugs that affect blood pressure are important therapeutic agents, and calcium channel blockers have been validated in a number of large clinical trials as effective in not only lowering blood pressure but also in reducing the risks of coronary heart disease and stroke. Although they are generally thought to preferentially block L-type calcium channels in the vascular system, some of them have also been reported to block T-type calcium channels as well. We propose to investigate the binding determinants and molecular basis of inhibition of three calcium channel blockers: mibefradil, as a prototype drug for which the T-type calcium channel is the primary target, verapamil, a first generation calcium channel blocker (phenylalkylamine), which continues to be effective for treatment of hypertension and also is a first line therapy for paroxysmal atrial tachycardia, and amlodipine, a highly prescribed fourth generation dihydropyridine (DHP). Our experimental focus will be on the T-type calcium channel as an important primary or secondary target of these drugs, although we also propose to collaborate with an L-channel laboratory for comparative analysis between drugs and T- and L-channels and to study voltage dependent Na channels as a secondary target of mibefradil. Our long term goal is to understand the control of the molecular substrate of drugs that target cardiac ion channels, i.e. the structural bases of their state dependent affinities. We have chosen these three agents because they are classes of therapeutic agents that are relevant to or attractive for clinical use, interact with T-channels in distinct ways, and provide us with the opportunity to discover important structural determinants of kinetic function. Our strategy combines mutagenesis, whole cell, single channel, and gating current electrophysiology, and molecular modeling.
|
0.958 |
2008 |
Hanck, Dorothy A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Structure-Function of the Cardiac Sodium Channel
DESCRIPTION (provided by applicant): The central role of Na channels in excitable cells gives it a critical role in normal and abnormal behavior. Its gating is a complex system, and even modest dysfunction of gating results in debilitating disease or death. The long term goal of this proposal is to understand the structure and function of the cardiac Na channel as a key contributor to normal and abnormal excitation and conduction and as a target of drugs to treat arrhythmias. For the first time sufficient information is available that we can hope to connect the action of drugs to limit permeation with their action to affect gating. The goals of the proposal for the next five years are to 1) Identify the conformational changes of S6 segments during activation; 2) Identify conformational changes in S6 during fast inactivation and their relation to S4 movements; 3) Determine the molecular features of local anesthetic drug binding and the mechanism of action; and 4} Locate superficial residues on S6 and S5 helices in relation to S4 segments. The experiments proposed combine molecular techniques with electrophysiology, principally whole cell ionic and gating current recordings, and molecular modeling to identify conformational changes in the inner pore S5 and S6 segments in response to S4 voltage sensor movement and drug binding. A key element of the proposal is to integrate: experimental data, both our own and that of others, into a molecular model of the relationship between [unreadable]<[unreadable] drug binding, gating, and the conformation of the inner pore.
|
0.958 |
2009 — 2010 |
Hanck, Dorothy A. Sheets, Michael F (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Drug Therapy Targeted to the Voltage-Gated Sodium Channel
The overall aim of the application is to understand the fundamental basis of the interaction of local anesthetic/antiarrhythmic drugs (LA) with the cardiac voltage-gated sodium (Na) channel (NaV1.5). The experiments will use wild-type (WT) and site-directed mutant Na channels heterologously expressed in mammalian cells and oocytes combined with molecular modeling of the Na channel pore. Aim 1. The LA binding site in the pore. We hypothesize that binding of LA to DIV-Phe1759 directly interacts with DIIIS6 residues or indirectly by close-packed interactions between DIIIS6 and DIVS6 in the open/inactivated channel configuration that results in stabilization of the DIIIS4. In this aim we propose to further explore drug interactions with the Na channel inner pore between S6's in DIV and DIII and stabilization of their corresponding S4's. In pursuance of this hypothesis we will determine the role of DIII-Leu1461 in the coupling of DIV to DIII. Aim 2: The link between fast inactivation and LA affinity. We hypothesize that binding of the fast inactivation lid is obligatory for stabilizing the high-affinity drug/channel interaction. In this aim we propose to determine how fast inactivation contributes to high affinity LA block by correlating the size and flexibility of LA and anticonvulsant drugs to their EC50's in mutant channels with fast inactivation removed by mutagenesis of the inactivation lid and by investigating the basis of the recently reported lidocaine-induced Brugada Syndrome NaV1.5 channelopathy, V232I+L1308F. Aim 3. LA interactions with the closed channel and with early steps in activation. We hypothesize that the opening of the Na channel pore formed by the S6 segments is passive, and that drug binding to the closed channel modestly stabilizes this configuration. In pursuance of this hypothesis we will determine the residues at the bundle crossing by crosslinking Cys substitutions between S6 segments.
|
0.958 |